In the past, various attempts have been made by numerous investigators in the field of organic medicinal chemistry to obtain new and better oral antidiabetic agents. Many of these efforts have involved the syntheses and testing of various new and unavailable organic compounds, particularly in the area of the sulfonylureas, in an endeavor to determine their ability to lower blood sugar (i.e., glucose) levels to a substantially high degree when given by the oral route of administration. The effect of other organic compounds in preventing or arresting certain chronic complications of diabetes, such as diabetic cataracts, neuropathy and retinopathy, etc. has also been studied. For example, K. Sestanj et al. in U.S. Pat. No. 3,821,383 discloses that certain aldose reductase inhibitors like 1,3-dioxo-1H-benz[d,e]isoquinoline-2(3H)-acetic acid and some closely related derivatives thereof are useful for these purposes, even though these particular compounds are not known to be hypoglycemic in nature.
In addition, for example, commonly assigned U.S. Pat. No. 4,130,714 entitled "Hydantoin Therapeutic Agents" the disclosure of which is hereby incorporated by reference discloses dextrorotatory spiro-hydantoin compounds such as d-6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione and d-6'-fluoro-spiroimidazolidine-4,4'-thiochroman-2,5-dione.
Non-hydantoin compounds previously reported to inhibit aldose reductase include 1H-benz[d,e]isoquinoline-1,3(2H)-dione-2-acetic acid derivatives, Sestanj et al., U.S. Pat. No. 3,821,383; halogen substituted chroman-4-carboxylic and chroman-4-acetic acids, Belletire, U.S. Pat. No. 4,210,663; spiro-[chroman-4,5'-oxazolidin]-2',3'-diones, Schnur, U.S. Pat. No. 4,200,642; and variously substituted phthalazin-1(2H)-on-4-acetic acids, Larson et al., published European Patent Application No. 222,576.
These aldose reductase inhibitors all function by inhibiting the activity of the enzyme aldose reductase, which is primarily responsible for regulating the reduction of aldoses (like glucose and galactose) to the corresponding polyols (such as sorbitol and galactitol) in the human body. In this way, unwanted accumulations of galactitol in the lens of galactosemic subjects, and of sorbitol in the lens, peripheral nervous cord and kidney of various diabetic subjects, are thereby reduced or prevented. As a result, these compounds are of value as aldose reductase inhibitors for controlling chronic diabetic complications, including but not restricted to those of an ocular nature, since it is known that the presence of polyols in an eye lens invariably leads to cataract formation and a loss of lens clarity.
Although compounds such as the hydantoins have proven useful for the treatment of diabetic complications there is a continuing search in this field of art for different, more effective inhibitors for the treatment of diabetic complications.